Towards Safe and Efficacious Medical Therapy for Patients with Clinically Non-Functioning Pituitary Tumors

Clinically non-functioning pituitary tumors (CNFTs) account for one-third of all pituitary adenomas. Unlike functioning lactotroph, somatotroph and corticotroph pituitary tumors, the majority of CNFTs derive from the gonadotroph cell lineage (~70%) and do not typically cause clinical and/or biochemical evidence of tumor- related hormone hypersecretion. Instead, they grow insidiously and present with mass effect symptoms such as headache, visual field deficits and hypopituitarism. Surgical resection is the current standard of care for gonadotroph tumors, but complete resection is infrequently achieved due to their size and invariable invasion of locally adjacent structures. Regrowth of the residual tumor occurs in approximately 50% of patients who then may need repeated surgeries and/or radiotherapy. The latter is quite effective in achieving tumor control but carries a risk of hypopituitarism of ~ 40% at 10 years. There are currently no approved medical treatments for gonadotroph tumors, and there is a clear unmet need for novel safe and effective medical therapies for these comparatively common tumors. In this highly innovative project, we will combine our unique patient- derived 3D gonadotroph tumoroid model with an automated high throughput screen (HTS) to identify novel tumoricidal and growth inhibitory compounds for gonadotroph tumors. Aim 1 of our proposal will quantitate inhibition of cell viability as primary endpoint in our high throughput screen to identify small molecules that specifically and efficiently target gonadotroph tumors. Hits will be defined using robust z-score statistics. Potential hits will then be reassessed by a series of orthogonal assays to corroborate their inhibition of cell viability. Compounds that emerge from these rigorous confirmation evaluations will be considered as primary hits. A second aim will use a cascade of follow-up assays including dose response curves, toxicity profiling, pharmacophore modeling, potency analysis and drug-likeness property evaluation to characterize the primary hit compounds. Thereafter, we will combine in-silicon target prediction with a series of complimentary overlapping experimental approaches to deconvolute the mode of actions of the resultant hits. Transcriptome profiling by RNA-seq will be used to segregate drug target pathways which will then be corroborated by pathway disruption using siRNA, shRNA, or CRISPR sub-libraries in combination with cDNA clones. In summary, we are confident that our rigorous HTS using our unique human gonadotroph tumoroids will enable us to find and characterize potent and efficacious disease-targeted small molecule compounds that can be ready for further study and development. Project Number: 1R01CA295582-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: ANTHONY HEANEY (+1 co-PI) | Institution: UNIVERSITY OF CALIFORNIA LOS ANGELES, LOS ANGELES, CA | Award Amount: $475,401 | Activity Code: R01 | Study Section: Drug Discovery and Molecular Pharmacology C Study Section[DMPC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11368926